ADDITION OF LENALIDOMIDE TO R‐CHOP (R2CHOP) IMPROVES OUTCOMES IN NEWLY DIAGNOSED DIFFUSE LARGE B‐CELL LYMPHOMA (DLBCL): FIRST REPORT OF ECOG‐ACRIN1412 A RANDOMIZED PHASE 2 US INTERGROUP STUDY OF R2CHOP VS R‐CHOP

Abstract

Introduction: Lenalidomide has single-agent activity in relapsed DLBCL. Single arm phase I/II trials of lenalidomide with RCHOP (R2CHOP) for untreated DLBCL have shown the regimen to be safe with promising activity, particularly in the activated B-cell-like (ABC) subtype. ECOG-ACRIN trial 1412 (E1412) is a randomized phase II study comparing R2CHOP vs R-CHOP in previously untreated DLBCL. Methods: Eligible patients were ≥ 18 years, with pathlogically confirmed DLBCL regardless of COO, stage II bulky-IV disease, IPI ≥ 2, ECOG PS ≤ 2 and measurable disease. Patients were randomized 1:1 and stratified by International Prognostic Index (2/3 vs 4/5) and age (<60 vs ≥ 60 y) to lenalidomide PO 25 mg/d, d1-10 q21d + standard RCHOP21 vs RCHOP21 for 6 cycles. Paraffin-embedded tumor tissue from the initial biopsy were analyzed using the NanoString Lymph2Cx GEP assay allowing for outcome analysis in ABC DLBCL. The primary endpoint was progression-free survival (PFS). With anticipated 289 evaluable patients ( 102 ABC-DLBCL), the study was designed to have 89% power at one-sided 0.1 significance level with 89 PFS events for testing in all patients, and 81% power at one-sided 0.125 significance level with 40 PFS events in ABC DLBCL. Secondary endpoints included response rate and overall survival (OS). Kaplan Meier method was used to estimate PFS and OS, stratified log-rank test and Cox model were used to compare between arms and estimate hazard ratios (HR). Results: 349 patients were enrolled between 8/2013 to 1/2017; 280 patients (145 R2CHOP, 135 RCHOP) were evaluable (ineligibility was primarly due to central pathology exclusion or lack of diagnostic material for central review); 94 were ABC-DLBCL; 122 GCB-DLBCL and 18 Unclassfied. Baseline patient characteristics are balanced between arms, median age 66 (range 24-92); 61% male; 88% white; 70% stage IV; 34%, 43% and 24% IPI 2, 3 and 4/5, respectively. Toxicity was as expected with R-CHOP; significantly different rates of grade >3 adverse events between arms were: diarrhea (6% vs. 0.6% of patients, p=0.005), febrile neutropenia (25% vs. 12% of patients, p=0.003), and thrombocytopenia ( 36% vs. 12% of patients, p<.0001) in R2CHOP vs R-CHOP arm, respectively. 86% and 85% patients completed 6 cycles of therapy in R2CHOP and RCHOP arms respectively. The overall and complete response rates were 92% and 67% in R-CHOP and 97% (p=0.12) and 72% (p=0.44) in R2-CHOP arm, respectively. With a median follow-up was 2.4 years; R2CHOP was associated with a 33% reduction in risk of progression or death vs RCHOP, HR 0.67 (95% CI 0.44- 1.03), p (one-sided) =0.03 (Figure). The 2-year overall survival was 87% and 80%, respectively. Based on COO, PFS HR for R2CHOP was: 0.68 for ABC, p=0.15, 0.86 for GCB, 0.83 for Unclassified and 0.61 for unknown cases. Keywords: diffuse large B-cell lymphoma (DLBCL); gene expression profile (GEP); immunochemotherapy. Discloures: Nowakowski, G: Celgene consultancy (personally uncompensated) and research support; MorphoSys consultancy (personally uncompensated), research support, Bayer: consultancy (personally uncompensated) and research support, Curis: research support, Roche: Research support, Genentech: Research support, NanoStrings Technologies: research support. Scott, DW: Named inventor on a patent licensed to NanoString Technologies [Institution], Research funding: Janssen, Roche/Genentech, NanoString Technologies, Consulting: Janssen, Travel: Celgene. Macon, R: Celgene research support. Leonard, JP: Consulting: Sutro, Bayer, Gilead, AstraZeneca, Celgene, Merck, Morphosys, Beigene, Nordic Nanovector, Roche/Genentech, ADC Therapeutics, Sandoz, Karyopharm, Miltenyi, Akcea Therapeutics. Kostakoglu, L: Roche/Gentech: Research support. Kahl, BS: Consulting: Celgene, Genentech, Roche, AbbVie, Pharmacyclics, Astra Zeneca. Witzig, TE: Research support: Celgene, Spectrum, Acerta, Consulting (personally uncompensated): Incyte, Seattle Genetics, Abbvie, Morphosys, Spectrum, Celgene. Consulting personaly compensated: Immune Design, Karyopharm.